The <i>APOE ε4</i> exerts differential effects on familial and other subtypes of Alzheimer's disease

Jia, Longfei; Xu, Hui; Chen, Shuoqi; Wang, Xiu; Yang, Jun; Gong, Min; Wei, Cuibai; Tang, Yi; Qu, Qing; Chu, Lan; Shen, Lu; Zhou, Chunkui; Wang, Qi; Zhao, Tan; Zhou, Aihong; Li, Ying; Li, Fangyu; Li, Yan; Jin, Hongmei; Qin, Qi; Jiao, Haishan; Zhang, Heng; Lyu, Diyang; Shi, Yuqing; Yang, Song; Jia, Jianping

doi:10.1002/alz.12153

Cited by 33 publications

(30 citation statements)

References 43 publications

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“…One copy of the APOE ε4 allele may increase the risk of AD by 2–6 times [ 90 ]. In our study, in the D homozygotes, the presence of APOE ε4 increased the risk of AD around 7.06-fold, much higher than that identified in the I homozygotes.…”

Section: Discussionmentioning

confidence: 99%

Angiotensin-converting enzyme polymorphisms AND Alzheimer’s disease susceptibility: An updated meta-analysis

et al. 2021

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Background Many studies among different ethnic populations suggested that angiotensin converting enzyme (ACE) gene polymorphisms were associated with susceptibility to Alzheimer’s disease (AD). However, the results remained inconclusive. In the present meta-analysis, we aimed to clarify the effect of ACE polymorphisms on AD risk using all available relevant data. Methods Systemic literature searches were performed using PubMed, Embase, Alzgene and China National Knowledge Infrastructure (CNKI). Relevant data were abstracted according to predefined criteria. Results Totally, 82 independent cohorts from 65 studies were included, focusing on five candidate polymorphisms. For rs1799752 polymorphism, in overall analyses, the insertion (I) allele conferred increased risk to AD compared to the deletion (D) allele (I vs. D: OR = 1.091, 95% CI = 1.007–1.181, p = 0.032); while the I carriers showed increased AD susceptibility compared with the D homozygotes (II + ID vs. DD: OR = 1.131, 95% CI = 1.008–1.270, p = 0.036). However, none of the positive results passed FDR adjustment. In subgroup analysis restricted to late-onset individuals, the associations between rs1799752 polymorphism and AD risk were identified using allelic comparison (OR = 1.154, 95% CI = 1.028–1.295, p = 0.015, FDR = 0.020), homozygotes comparison, dominant model and recessive model (II vs. ID + DD: OR = 1.272, 95% CI = 1.120–1.444, p < 0.001, FDR < 0.001). Nevertheless, no significant association could be revealed after excluding studies not in accordance with Hardy-Weinberg equilibrium (HWE). In North Europeans, but not in East Asians, the I allele demonstrated increased AD susceptibility compared to the D allele (OR = 1.096, 95% CI = 1.021–1.178, p = 0.012, FDR = 0.039). After excluding HWE-deviated cohorts, significant associations were also revealed under homozygotes comparison, additive model (ID vs. DD: OR = 1.266, 95% CI = 1.045–1.534, p = 0.016, FDR = 0.024) and dominant model (II + ID vs. DD: OR = 1.197, 95% CI = 1.062–1.350, p = 0.003, FDR = 0.018) in North Europeans. With regard to rs1800764 polymorphism, significant associations were identified particularly in subgroup of European descent under allelic comparison (T vs. C: OR = 1.063, 95% CI = 1.008–1.120, p = 0.023, FDR = 0.046), additive model and dominant model (TT + TC vs. CC: OR = 1.116, 95% CI = 1.018–1.222, p = 0.019, FDR = 0.046). But after excluding studies not satisfying HWE, all these associations disappeared. No significant associations were detected for rs4343, rs4291 and rs4309 polymorphisms in any genetic model. Conclusions Our results suggested the significant but modest associations between rs1799752 polymorphism and risk to AD in North Europeans. While rs4343, rs4291 and rs4309 polymorphisms are unlikely to be major factors in AD development in our research.

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Section: Discussionmentioning

confidence: 99%

Angiotensin-converting enzyme polymorphisms AND Alzheimer’s disease susceptibility: An updated meta-analysis

et al. 2021

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“…One copy of the APOE ε4 allele may increase the risk of AD by 2-6 times [90]. In our study, in the D homozygotes, the presence of APOE ε4 increased the risk of AD around…”

Section: Plos Onesupporting

confidence: 46%

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“…Thus, the genetic architecture of AD is expected to be dominated by thousands of small-effect variants that each slightly perturb brain physiology toward a more AD-susceptible state, rather than a small set of highly penetrant mutations. Indeed, even the well-studied APOE-E4 risk allele has an odds ratio of only 11.8 in the Caucasian population, which is by no means a certainty for any carrier (Jia et al, 2020). The value of genetic network analysis to the study of the architecture of complex disease, therefore, is to aggregate these many small perturbations into a pathway-and process-level description of the full disease.…”

Section: Discussionmentioning

confidence: 99%

System-Level Analysis of Alzheimer’s Disease Prioritizes Candidate Genes for Neurodegeneration

et al. 2021

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Alzheimer’s disease (AD) is a debilitating neurodegenerative disorder. Since the advent of the genome-wide association study (GWAS) we have come to understand much about the genes involved in AD heritability and pathophysiology. Large case-control meta-GWAS studies have increased our ability to prioritize weaker effect alleles, while the recent development of network-based functional prediction has provided a mechanism by which we can use machine learning to reprioritize GWAS hits in the functional context of relevant brain tissues like the hippocampus and amygdala. In parallel with these developments, groups like the Alzheimer’s Disease Neuroimaging Initiative (ADNI) have compiled rich compendia of AD patient data including genotype and biomarker information, including derived volume measures for relevant structures like the hippocampus and the amygdala. In this study we wanted to identify genes involved in AD-related atrophy of these two structures, which are often critically impaired over the course of the disease. To do this we developed a combined score prioritization method which uses the cumulative distribution function of a gene’s functional and positional score, to prioritize top genes that not only segregate with disease status, but also with hippocampal and amygdalar atrophy. Our method identified a mix of genes that had previously been identified in AD GWAS including APOE, TOMM40, and NECTIN2(PVRL2) and several others that have not been identified in AD genetic studies, but play integral roles in AD-effected functional pathways including IQSEC1, PFN1, and PAK2. Our findings support the viability of our novel combined score as a method for prioritizing region- and even cell-specific AD risk genes.

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The APOE ε4 exerts differential effects on familial and other subtypes of Alzheimer's disease

Cited by 33 publications

References 43 publications

Angiotensin-converting enzyme polymorphisms AND Alzheimer’s disease susceptibility: An updated meta-analysis

Angiotensin-converting enzyme polymorphisms AND Alzheimer’s disease susceptibility: An updated meta-analysis

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System-Level Analysis of Alzheimer’s Disease Prioritizes Candidate Genes for Neurodegeneration

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